HAVCR2 and neoplasm: On the other hand, acquired resistance may result from clonal selection of tumor sub-populations lacking neoantigens, epigenetic or signaling pathway changes (e.g., JAK1/JAK2 mutations, IFN-γ pathway defects), upregulation of alternative immune checkpoints (e.g., TIM-3, LAG-3) and remodelling of the tumor microenvironment to a “cold” phenotype.